RIMTAC: A Novel Degrader Design Platform by Indirect VHL-Recruitment via RIPK1

Proteolysis-targeting chimeras (PROTACs) have emerged as a transformative approach for targeted protein degradation (TPD). However, their therapeutic potential is limited by the scarcity of diverse E3 ligase ligands. Only a small fraction of more than 600 human E3 ligases are currently amenable to functional PROTAC development. To expand the E3 ligase toolbox, we developed RIPK1-Mediated Targeting Chimeras (RIMTAC). Rather than directly inhibiting VHL, RIMTAC employs a RIPK1 inhibitor to hijack the endogenous RIPK1-VHL complex, recruiting VHL indirectly for TPD. As a proof of concept, we designed RIMTACs targeting BRD4, AKT, and JAK1. These molecules induced potent, concentration- and time-dependent degradation of their targets. Mechanistically, degradation was confirmed to be UPS-dependent and required a quaternary complex of VHL, RIPK1, the target protein, and the RIMTAC molecule. RIMTAC expands the TPD toolbox and offers a promising synergistic strategy for anti-inflammatory therapy.